X-rays reveal clues to prevent juvenile diabetes

Juvenile diabetes, which currently affects more than 700,000 Americans, may be at least one step closer to prevention as a result of recent research performed at Argonne’s Advanced Photon Source (APS).

Important clues found in the research may lead to both cures for and prevention of the disease, formally known as Type 1 diabetes or insulin-dependent diabetes mellitus.

Researchers from Children’s Hospital of Boston, the Howard Hughes Medical Institute and the Dana-Farber Cancer Institute discovered the clues, which indicate that juvenile diabetes may be prevented in those people who carry genes for it. Research is still needed into how that will be done, but these results show that prevention is possible and indicate the areas of the DNA where preventive techniques would be effective.

Juvenile diabetes is a chronic condition in which the pancreas makes little or no insulin because certain cells have been destroyed due to an autoimmune disorder. The pancreatic islet cells, or "beta" cells, that produce insulin are mistakenly seen by the body as an "enemy." The body then creates antibodies (or antigens) to fight the "foreign" tissue. These antigens destroy the islet cells’ insulin-producing capacity and the resulting lack of insulin brings on diabetes.

Symptoms of juvenile diabetes appear abruptly, although the damage to the beta cells may begin well before the disease becomes apparent. Prevention of the disease requires a thorough understanding of what biological differences trigger the autoimmune response against pancreatic islet cells. To gain that understanding, researchers need to know the structures and binding mechanisms of protein molecules that produce the antigens. This research advances that understanding.

Research has shown that juvenile diabetes sufferers carry certain genes coded for cell-surface proteins important in the production of islet cell antigens. In humans, these are called Major Histocompatibility Complex glycoproteins HLA-DQ8 and HLA-DQ2; similar genes are coded for proteins in mice, and are called I-Ag7.

However, scientists don’t yet know how these genes spark the destruction of insulin-producing cells.

The researchers applied X-ray crystallography techniques at the APS beamline managed by the Biological Consortium for Advanced Radiation Sources Collaborative Access Team.

They determined the three-dimensional structure of the glycoproteins and peptides — the molecules that hydrolyze into amino acids and form the basic building blocks of proteins — from insulin.

They have analyzed the size and composition of the peptide-binding pockets of the human proteins compared to the mouse proteins.

The resulting similarities suggest that both humans and mice develop juvenile diabetes in the same way.

This discovery provides evidence that the mouse is a good model for the human disease and can be used as a test subject for research into prevention of juvenile diabetes, opening the way to aggressive research on prevention and treatment of the disease.

Their research was funded by the National Institutes of Health and the Howard Hughes Medical Institute.

For more information please contact Catherine Foster